Extra-Nodal Lymphomas of the Head and Neck and Oral Cavity: A Retrospective Study

Round 1

Reviewer 1 Report

The study by Alfonso Sorrentino et al. contains a really good dataset, which raised my interest. The manuscript presents interesting data and could be considered for publication if the responses to revisions are satisfactory:

1.     The author mention LCA, CD20, CD3, CD30, CD10 and CD13 were used for histological diagnosis. Could the authors provide more detailed information on the markers they used for histological diagnosis of different types of lymphomas?

2.     2.1. Search strategy. The authors provide much information about the diagnosis procedure; I am not sure everything is needed. Please make sure you clearly and concisely describe how the patients were recruited, diagnosed, and followed up, and if possible, eliminate extra information. If you find it useful, please subdivide the section into two subsections for recruitment/diagnosis and treatment/follow-up. Otherwise, at least split it into paragraphs to facilitate reading. 

I suggest renaming this section to something more accurately defines what you are describing, which to my understanding, is mainly patient recruitment and the diagnosis procedure. Please indicate the meaning of any abbreviation like CT and MRI since no medical readers can find it difficult to follow you.

3.     Data presentation should improve. You can take these suggestions or arrange your data in any other way that is better presented:

a) Merge Table 1 and Table 2. You can add more demographic information to this new table (age, survival), so your data is nicely presented here instead of in the text.

b) For Table 3, can the authors indicate localization (oral, no oral) by lymphoma type? Like in Table 4 but displaying the specific site (palate, tongue, tonsil, etc.). This brings me to the next point.

4.     I don't understand what is presented in Table 4 regarding 'location after 5 years of follow-up'. Please clarify. Also, you can indicate directly in the table the statistically significant difference in the death you found to be more precise about which groups you are comparing by Fisher's exact test.

5.     In the discussion section, please focus on comparing your results with previous studies instead of providing background on lymphomas. You can move that background to the introduction if you want. 

6.     2.2 Trial procedures. Please provide the protocol number of your study.

Author Response

First of all, thank you for the comments and insights provided. The requested changes have all been applied to our manuscript.

1. More detailed information on the markers used for immunohistochemical analysis has been included in the "Introduction" section. A reference immunohistochemical panel was also inserted which is used in the diagnosis of lymphomas.
2. The additional and unnecessary information in the "Materials and Methods" section has been deleted. Furthermore, it has been divided into the subsections "Recruitment & Diagnosis" and "Treatment & Follow-up". In this way, the methodology for enrolling patients and the diagnostic methods used were described more clearly.
3. Tables 2 and Table 3 in the "Results" section have been modified, reporting in detail the data relating to the histological type of ENHL and the localization (for both groups, oral and non-oral). The data is also clearly and concisely illustrated in the text as well.
4. Table 4 (related to Survival at 5 years of follow-up) has been extensively modified to include surviving and non-surviving patients, and histological types of ENHLs. Statistical analysis relating to survival was performed using the Kaplan Meier curve with the log-rank test.
5. Much of the lymphoma background information content has been moved from the "Discussion" section to the "Introduction" section, as suggested by the Reviewer. Furthermore, the results obtained have been described in more detail in the "Discussion" section.
6. The Protocol number of the Study has been inserted in the text.

Furthermore, the authors have been modified as follows: Author Ferragina F as first author and corresponding author; Author Arrotta A. has been added.

Author Response File: Author Response.docx

Reviewer 2 Report

In this paper by Sorrentino et al, the clinico-demographic patterns of extra nodal lymphomas in the head and neck region are described. This is an interesting series but several issues remain. There is lack of data on whether patients received chemotherapy, the reporting of the survival data needs significant improvement. In summary, if this series is to have a meaningful impact, it needs to address the following:

MAJOR comments:

1. How many patients received RCHOP (in the NHL arm), and ABVD in the HL arm? If there was a significant group of patients who did not receive chemotherapy, then statistical power allowing, was there a difference in outcomes?

2. They talk about the "death rate". It might be best to describe their findings as median OS, and OS at 2 years and OS at 5 years and a Kaplan Meier curve here would be helpful. We don't typically use fisher exact test to determine survival probabilities. 

3.  How many patients had EBV positivity?

Author Response

First of all, thank you for the comments and insights provided. The requested changes have all been applied to our manuscript.

1. All patients with ENHL underwent chemotherapy treatment according to the R-CHOP scheme (as better specified in the text). Patients with HL were not included in the study; only the number and the percentage are reported.
2. To determine the significance of the survival study, a Kaplan–Meier analysis with the log-rank test was performed.
3. All patients underwent laboratory tests for known infectious risk factors (HIV, HCV, HBV and EBV), and none of them tested positive for EBV.

Furthermore, the authors have been modified as follows: Author Ferragina F as the first author and corresponding author; Author Arrotta A. has been added.

Round 2

Reviewer 1 Report

The authors have improved their manuscript significantly and it is ready for publication.

Author Response

All changes requested by the reviewers have been applied to the manuscript

Author Response File: Author Response.docx